Elevated pulmonary microvascular pressures and high lung vascular permeability are two causes of pulmonary edema. I wish to study the effects of thromboxane A2 on pulmonary vascular resistance and lung vascular permeability to determine whether thromboxane synthesis contributes to the pathogenesis of pulmonary edema. Escherichia coli endotoxin infused into sheep causes initial severe pulmonary hypertension followed by a steady state period of high lung vascular permeability which can result in pulmonary edema. Endotoxin stimulates thromboxane biosynthesis, and preliminary experiments have shown that imidazole, a selective inhibitor of thromboxane synthetase, inhibits pulmonary vascular responses of sheep to endotoxin. Whether or not thromboxane synthesis is required for full expression of the sheep reaction to endotoxin will be determined in further experiments with imidazole and other inhibitors of thromboxane synthetase. Measurements of lymph thromboxane B2 concentrations will allow evaluation of the in vivo effectiveness of thromboxane synthetase inhibitors with the advantage that the contribution of collection artifact may be minimized due to the relative absence of platelets in lymph compared to blood. The direct pulmonary vascular effects of thromboxane A2 will be studied in sheep by comparing responses to continuous intravenous infusions of 14C-prostaglandin H2 in the presence and absence of thromboxane synthetase from washed platelet particles. Metabolism of infused 14C-prostaglandin H2 to radiolabeled thromboxane B2 and several prostaglandins will be analyzed by thin layer chromatography of lung lymph extracts. Data obtained from these experiments will identify and quantitate the major metabolites produced from prostaglandin endoperoxide infused in the lung.